OBJECTIVE: Wnt/β-catenin signaling is related to the pathogenesis of several diseases. Sclerostin is an inhibitor of Wnt/β-catenin signaling. However, there are few data regarding the sclerostin levels and vascular disease. Our aim was to examine the relationship between serum sclerostin and atherosclerotic disease (AD) in type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: We performed a cross-sectional study including 78 T2DM patients (45.3% females, mean age 59 ± 5.7 years; 54.7% males, 57.4 ± 6.7 years). RESULTS: Serum sclerostin concentrations of T2DM patients in the AD group were significantly higher than in the non-AD group (P = 0.006). For each increase of 1 pmol/L in sclerostin level, there was a 4% increase of the risk of AD in T2DM patients. A concentration of ≥42.3 pmol/L showed a sensitivity of 69% and a specificity of 54.8% to detect an increased risk of AD. In males, sclerostin levels were higher in those with AD (P = 0.04), abnormal intima-media thickness (IMT) (P = 0.004), carotid plaques (P < 0.001), and aortic calcification (P < 0.001). In females, higher levels of sclerostin were related to abnormal IMT (P = 0.03) and aortic calcifications (P = 0.004). Homocysteine (β = 0.319 [95% CI 0.561–2.586], P = 0.003) and IMT (β = 0.330 [14.237–67.693], P = 0.003) were positively correlated with sclerostin. CONCLUSIONS: Circulating sclerostin is increased in T2DM patients with atherosclerotic lesions. Although the sample size of our study was small, these data suggest that sclerostin levels could be a major modulator of Wnt signaling in AD with implications in T2DM patients.